Cancer is still one of the most difficult diseases to understand, diagnose and treat. After decades of intense research interest, the causes and prevention of this disease or these diseases remain elusive, despite several notable advances in our knowledge of the physiological processes that underlie the disease.
One of the reasons for the lack of understanding of cancer or its adequate treatment is that it is manifested in various physical states. Cancer can occur as diffuse cells, e.g. the leukemias, or as solid tumors. The solid tumors can reside at various anatomic locations or sites within the body. These tumors can exist within or be contiguous to an organ that is normally found within the body.
The solid tumors quickly acquire their own blood supply and vasculature (arterioles, capillaries and venules) when they have achieved a minimum size (otherwise they use the body""s normal blood supply and vasculature). This tumor blood vasculature has some properties that resemble those for the vasculature of normal organs of the body. However, the vasculature of solid tumors also has properties that are dissimilar from that of normal organs. The distribution of blood vessels is not uniform in solid tumors. The vasculature of solid tumors can have tortuous pathways, blind terminations and abnormal shunts between the arterial and the venous portions of the vasculature. Blood flow is markedly slowed in the blood vessels in solid tumors. The viscosity of the blood in the vasculature of solid tumors also appears to be higher than that for blood in normal tissues. In addition, vessel walls within solid tumors can be leaky to molecules contained within the bloodstream or they can be quite impervious to such molecules. Often, the leakiness and imperviousness occur within the same blood vessel within the same solid tumor.
Another unique feature of solid tumors is the high interstitial pressure that exists in comparison to the interstitial pressure in normal organs. The pressure for fluid flow that exists within the spaces that surround the cells that comprise the solid tumor is much higher in the internal spaces of the tumor than within the internal spaces of normal tissues and organs. The high interstitial pressure in the internal spaces of solid tumors greatly retards the movement of molecules that are present in the bloodstream into the internal spaces of solid tumors. This retardation particularly affects those molecules that are transported from the bloodstream into the internal spaces of solid tumors primarily by the movement of the molecules down a pressure gradient from the bloodstream to the interstitial spaces of the solid tumor. Because of the high interstitial pressure in solid tumors, such movement becomes much slower or nonexistent.
For the above reasons, the delivery of therapeutic or diagnostic molecules from the bloodstream to the internal spaces of solid tumors, particularly non-central nervous system solid tumors, does not readily occur. At the present time, it is difficult to deliver therapeutic or diagnostic pharmaceuticals to the tumor cells that constitute solid tumors. It is likewise difficult to maintain sufficient amounts of such pharmaceuticals in the vicinity of the tumor cells long enough for the tumor cells to be affected by the pharmaceuticals. Primarily, this is because tumor cells of the solid tumors reside in the extravascular region, often at some distance from a given blood vessel in these tumors.
It is readily apparent that improved delivery of molecules, particularly therapeutic or diagnostic pharmaceutical molecules, from the bloodstream to the internal spaces of solid tumors, would be an advancement in the diagnosis and treatment of these solid tumors. This is particularly true for the delivery of molecules to the internal spaces of non-central nervous system solid tumors. The administration of such molecules into the bloodstream of the host followed by their transport to the internal spaces of solid tumors would be a significant gain in solid tumor treatment and diagnosis. This delivery procedure would be much less invasive than the physical administration of these molecules directly into the solid tumor mass with subsequent loss from the tumor to the bloodstream.
The present invention pertains to a method of increasing the transport of a molecule from the bloodstream of a host to the internal spaces of a non-central nervous system solid tumor that is present in the host. This method comprises intravascular co-administration to the host of an effective amount of an agent that increases such transport of the molecule. The molecule to be delivered to the tumor can be an endogenous molecule or an exogenous molecule that is co-administered sequentially or simultaneously with the agent.
An advantage of the present invention is that it provides a practical means of increasing the transport of a molecule from the bloodstream to the internal spaces of a non-central nervous system solid tumor by the intravascular administration of the agent while co-administering a molecule of therapeutic, prophylactic or diagnostic value.
Preferred agents are bradykinin agonists. Particularly preferred bradykinin agonists are compositions which are peptides having a core sequence of amino acids or amino acid analogs. In the core peptide, the sequence is arginine-proline-hydroxyproline-glycine-thienylalanine-serine-proline-4-Me-tyrosine"psgr"(CH2NH)arginine (Seq. ID No: 1), from N-terminal to C-terminal, where CH2NH denotes a reduced peptide bond between the 4-Me-tyrosine and arginine amino acids. This peptide, which is an analog of bradykinin, is referred to herein, for convenience, as Cereport(trademark). Conformational analogs of this, sequence are also preferred bradykinin agonists, provided they have the property of increasing the transport of a molecule from the bloodstream of a host to the internal spaces of a non-central nervous system solid tumor.